Regulatory role of the endocannabinoid system on glial cells toward cognitive function in Alzheimer's disease: A systematic review and meta-analysis of animal studies

Mohd Amir Kamaruzzaman; Muhammad Hibatullah Romli; Razif Abas; Sharmili Vidyadaran; Mohamad Taufik Hidayat Baharuldin; Muhammad Luqman Nasaruddin; Vishnumukkala Thirupathirao; Sreenivasulu Sura; Kabul Warsito; Nurul Huda Mohd Nor; Muhammad Amsyar Azwaruddin; Mohammed Abdullah Alshawsh; Mohamad Aris Mohd Moklas

doi:10.3389/fphar.2023.1053680

Regulatory role of the endocannabinoid system on glial cells toward cognitive function in Alzheimer's disease: A systematic review and meta-analysis of animal studies

Front Pharmacol. 2023 Mar 3:14:1053680. doi: 10.3389/fphar.2023.1053680. eCollection 2023.

Authors

Mohd Amir Kamaruzzaman^{1

2}, Muhammad Hibatullah Romli³, Razif Abas², Sharmili Vidyadaran⁴, Mohamad Taufik Hidayat Baharuldin⁵, Muhammad Luqman Nasaruddin⁶, Vishnumukkala Thirupathirao⁷, Sreenivasulu Sura^{2

8}, Kabul Warsito⁹, Nurul Huda Mohd Nor², Muhammad Amsyar Azwaruddin², Mohammed Abdullah Alshawsh^{10

11}, Mohamad Aris Mohd Moklas²

Affiliations

¹ Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
² Department of Human Anatomy, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Kuala Lumpur, Malaysia.
³ Department of Nursing and Rehabilitation, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Kuala Lumpur, Malaysia.
⁴ Department of Pathology, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Kuala Lumpur, Malaysia.
⁵ Department of Anatomy, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia, Kuala Lumpur, Malaysia.
⁶ Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
⁷ Department of Human Biology, International Medical University, Kuala Lumpur, Malaysia.
⁸ Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Kampar, Malaysia.
⁹ Department of Agrotechnology, Faculty of Science and Technology, University of Pembangunan Panca Budi, Medan, Indonesia.
¹⁰ Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.
¹¹ Department of Paediatrics, School of Clinical Sciences, Faculty of Medicine, Nursing and Health Science, Monash University, Clayton, VIC, Australia.

Abstract

Objective: Over the last decade, researchers have sought to develop novel medications against dementia. One potential agent under investigation is cannabinoids. This review systematically appraised and meta-analyzed published pre-clinical research on the mechanism of endocannabinoid system modulation in glial cells and their effects on cognitive function in animal models of Alzheimer's disease (AD). Methods: A systematic review complying with PRISMA guidelines was conducted. Six databases were searched: EBSCOHost, Scopus, PubMed, CINAHL, Cochrane, and Web of Science, using the keywords AD, cannabinoid, glial cells, and cognition. The methodological quality of each selected pre-clinical study was evaluated using the SYRCLE risk of bias tool. A random-effects model was applied to analyze the data and calculate the effect size, while I² and p-values were used to assess heterogeneity. Results: The analysis included 26 original articles describing (1050 rodents) with AD-like symptoms. Rodents treated with cannabinoid agonists showed significant reductions in escape latency (standard mean difference [SMD] = -1.26; 95% confidence interval [CI]: -1.77 to -0.76, p < 0.00001) and ability to discriminate novel objects (SMD = 1.40; 95% CI: 1.04 to 1.76, p < 0.00001) compared to the control group. Furthermore, a significant decrease in Aβ plaques (SMD = -0.91; 95% CI: -1.55 to -0.27, p = 0.006) was observed in the endocannabinoid-treated group compared to the control group. Trends were observed toward neuroprotection, as represented by decreased levels of glial cell markers including glial fibrillary acid protein (SMD = -1.47; 95% CI: -2.56 to -0.38, p = 0.008) and Iba1 (SMD = -1.67; 95% CI: -2.56 to -0.79, p = 0.0002). Studies on the wild-type mice demonstrated significantly decreased levels of pro-inflammatory markers TNF-α, IL-1, and IL-6 (SMD = -2.28; 95% CI: -3.15 to -1.41, p = 0.00001). Despite the non-significant decrease in pro-inflammatory marker levels in transgenic mice (SMD = -0.47; 95% CI: -1.03 to 0.08, p = 0.09), the result favored the endocannabinoid-treated group over the control group. Conclusion: The revised data suggested that endocannabinoid stimulation promotes cognitive function via modulation of glial cells by decreasing pro-inflammatory markers in AD-like rodent models. Thus, cannabinoid agents may be required to modulate the downstream chain of effect to enhance cognitive stability against concurrent neuroinflammation in AD. Population-based studies and well-designed clinical trials are required to characterize the acceptability and real-world effectiveness of cannabinoid agents. Systematic Review Registration: [https://inplasy.com/inplasy-2022-8-0094/], identifier [Inplasy Protocol 3770].

Keywords: Alzheimer’s disease; astrocyte; cognition; dementia; endocannabinoid; glial cell; microglia; systematic review.

Publication types

Systematic Review

Grants and funding

This work was supported by Universiti Putra Malaysia (UPM) who sponsored the research grants from the Ministry of Higher Education of Malaysia, namely, the Fundamental Research Grant Scheme (FRGS) (FRGS/1/2019/SKK08/UPM/02/16).